ESTRO 36 Abstract Book

S206

ESTRO 36

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SP-0381 Clinical challenges we currently face

E. Troost

TU Dresden- Med. Faculty Carl Gustav Carus,

Radiotherapy and Radiation Oncology, Dresden, Germany

Proton beam therapy poses numerous challenges to

modern radiotherapy. Aspects that will be discussed

during the lecture include: strategies for patient

selection, challenges irradiating moving targets, obstacles

arising from imaging modalities available at the gantry or

in the treatment room and outcome assessment.

Teaching Lecture: Targeting histones and epigenetic

mechanisms in radiation biology and oncology

SP-0382 Targeting histones and epigenetic mechanisms

in radiation biology and oncology

A.H. Ree

Akershus University Hospital, Department of Oncology,

Lørenskog, Norway

In modern radiation oncology, new insights into molecular

radiobiology provide an opportunity for the rational

integration of molecularly targeted therapeutics in

clinical radiotherapy in an effort to optimize radiation

effects. Recognizing the 4Rs of classic radiobiology –

reoxygenation, redistribution within the cell cycle,

recovery from DNA damage, and repopulation – each

contributing either to improved or impaired tumor control

in fractionated radiotherapy, an appealing strategy for

enhancing radiation efficacy may be to target

fundamental biological mechanisms governing all of the

processes. In that context, epigenetic modifications have

become a topic of renewed interest. DNA is normally

tightly wrapped in histone octamers to form nucleosomes,

dynamic structures that can be remodeled by a range of

molecular processes including DNA methylation and

methylation or acetylation of histones. Furthermore,

because epigenetic alterations can be reversed by certain

classes of drugs, they are interesting candidates as targets

for radiation sensitizers. For example, conveyed by

alterations in DNA methylation or histone acetylation

patterns, inhibitors of DNA methyltransferases or histone

deacetylases (HDAC) may cause perturbations in the

regulation of genes implicated in tumor hypoxia, cell cycle

progression, DNA damage repair, and cell death.

From our research program on HDAC inhibitors combined

with radiotherapy for colorectal cancer, we have

observed:

1. Enhanced radiation-induced suppression of tumor cell

clonogenicity

in vitro

2. Prolonged radiation-induced tumor growth delay of

normoxic and hypoxic

in vivo

models.

3. Histone hyperacetylation of patients’ tumors.

4. Clinical treatment responses.

5. Overlapping but acceptable toxicities from the two

treatment modalities.

6. Biological markers of treatment toxicity in patients’

surrogate tissue.

7. Normal tissue apoptosis and autophagy in experimental

models.

We initially reported on tumor cell radiosensitization and

associated cell cycle effects in human colorectal

carcinoma cell lines exposed to HDAC inhibitors. In human

colorectal carcinoma xenograft models, we observed

significant tumor growth delay following fractionated

radiation combined with daily injections of the mice with

the HDAC inhibitor vorinostat, compared to the radiation

treatment alone. Furthermore, there was a similar tumor

volume effect in irradiated hypoxic xenografts in mice

injected with vorinostat and xenografts irradiated under

normoxic conditions, demonstrating that the HDAC

inhibitor had counteracted the radioresistant hypoxic

phenotype.

Next, we conducted the Pelvic Radiation and Vorinostat

(PRAVO) phase 1 study. This trial for symptom palliation

in advanced gastrointestinal cancer was undertaken in

sequential patient cohorts exposed to escalating doses of

vorinostat combined with standard-fractionated palliative

radiotherapy to pelvic target volumes, and was the first to

report on the therapeutic use of an HDAC inhibitor in

clinical radiotherapy. It was designed to demonstrate that

vorinostat reached the radiotherapy target (detection of

tumor histone hyperacetylation) and the applicability of

non-invasive tumor response assessment (using functional

imaging). Following gene expression array analysis of

study patients’ peripheral blood mononuclear cells

(PBMC), we identified markers of vorinostat activity

related to cell cycle progression and reflecting the

appropriate timing of drug administration in the

fractionated radiotherapy protocol. Because common side

effects of vorinostat single-agent therapy include

intestinal toxicities, the primary objective of the PRAVO

study was to determine tolerability to vorinostat in

combination with pelvic radiation. Of note, in PBMC from

the patient cohort that specifically experienced dose-

limiting intestinal toxicities from vorinostat, genes

implicated in cell death were significantly enriched. Using

preclinical models at relevant drug concentrations,

apoptotic and autophagic features in cultured normal

intestinal epithelial cells and significant weight loss in

mice following administration of the compound were

observed as functional endpoints. These findings

underscored that apoptosis and autophagy may play a

central role in treatment toxicity from HDAC inhibitors

and should be taken into consideration in the clinical

context.

In conclusion, epigenetic mechanisms may be exploited in

radiation oncology. As illustrated by our research program

involving targeting of histone acetylation, the combined

clinical and translational approach for studying tumor

radiosensitization, systemic normal tissue responses, and

organ-confined radiation adverse effects may be part of a

template for future preclinical and early-phase clinical

studies assessing radiation combined with molecularly

targeted therapeutics in general and epigenetic modifiers

in particular.

Teaching Lecture: State of the art and future

improvements in in-room cone beam CT image quality

SP-0383 State of the art and future improvements for

in-room cone-beam CT image quality

D. Moseley

Princess Margaret Cancer Centre University Health

Network, Radiation Medicine Program, Toronto, Canada

Cone-beam CT systems are standard features on most

medical linear accelerators. These systems are routinely

used to deliver image-guided radiation therapy. The

"cone-beam" geometry presents several challenges for

computed tomography reconstruction. These challenges

are both due to the physics of the situation and

engineering limitations. These limitation include x-ray

scatter as well as object truncation due to a limited

FOV. In addition, a key component in the cone-beam CT

system is the amorphous silicone flat-panel detectors

which acquire the 2D projection images. These devices

have slower readout, increased image noise and increased

image lag as compared to slice-based helical CT detectors.

This talk will introduce some of the challenges to image

quality for in-room cone-beam CT. How do these

limitations affect their use in patient setup correction,